Drug craving (desire to re-experience effects of a psychoactive substance) is an internal motivational state that can be measured objectively. The mechanisms that underlie drug craving and mediate illicit drug-taking behavior are poorly understood, but are important to improving treatment and health status. The overall aim of this research is to determine the effects of several pharmacological and environmental variables on heroin craving in methadone-maintained clients. We have previously shown that naloxone-precipitated withdrawal in methadone clients is accompanied by increased heroin craving, using a new multifactor scale (Heroin Craving Questionnaire [HCQ]). These systematic and interrelated studies will extend our work on the determinants of craving during anticipation of drug reinforcement in methadone-malntained clients, in an effort to increase our understanding of the detenninants of drug craving and their clinical consequences. Specific questions are: (Study 1) Does methadone decrease opioid craving? Is craving reduction a function of time in treatment or medication dose? Do different methadone exposure histories produce differences in craving? Is methadone's effect on craving pharmacologically specific? Do individual differences methadone pharmacokinetics influence craving?(study 2) Do the magnitude/pattern of opioid craving and brain electrophysiology differ during anticipation of i.v. opioid self-administration under conditions of opioid withdrawal (negative reinforcement) versus after low priming doses of fentanyl (positive reinforcement)? Are these changes specific to receiving a drug, or do similar changes occur in preparation to receive other reinforcers (money)?; (Study 3) Do increases in the delay of methadone delivery increase opioid craving? Is craving attenuated by work activity during the delay period?; (Study 4) Does methadone availability alter heroin craving, i.e., do changes in the magnitude of the dose and probability of receiving a drug dose affect craving during anticipation of its delivery?; (All Studies) Do the a priori (conceptual) subscales vs. empirically-derived factor scores of the HCQ provide a more sensitive index of craving effects? These studies are responsive to the RFA and will be clinically useful. Broader insights into the affective, cognitive and behavioral components of drug incentive motivation are likely to result, and the behavioral principles and methods advanced here can guide future research on craving for cocaine and other drugs of abuse.